European Medicines Agency warns of deaths due to prolonged use of drugs combining codeine and ibuprofen

The health authority says the combination pain treatment can cause serious harm to the kidneys, particularly when taken at higher than recommended doses

A pharmacist holds up a box of Neobrufen, a drug that combines ibuprofen with codeine.PACO PUENTES (EL PAIS)

The European Medicines Agency (EMA) has issued a warning about the risks of long-term use of medicines containing ibuprofen and codeine. The joint intake of both active ingredients, which are used to treat pain, can cause “serious harms, including death, particularly when taken for prolonged periods at higher than recommended doses,” the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) warned in a September 30 alert.

The EMA stated that it has received news in recent months of several deaths related to codeine with ibuprofen combinations, although none of them have been recorded in Spain, according to the Spanish Agency for Medicines and Health Products (AEMPS). Treatments that combine ibuprofen and codeine can only be purchased with a prescription in Spain.

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) used to treat mild and moderate pain, among other ailments. Codeine is considered a mild opioid that can also be used for less intense pain. The combined use of both active ingredients is, in theory, an advantage: as their mechanisms of action are completely different, the use of both has a greater therapeutic effect and makes it possible to deal with moderate pain without having to resort to more potent opioids.

“The use of these drugs is only justified for short periods of time, because prolonged use has many side effects in addition to those now reported by the EMA. Codeine causes persistent constipation, and ibuprofen has a harsh effect on the digestive system. If pain becomes chronic, there are other effective and safer therapeutic options,” explained María Ángeles Canos, the head of the Pain Management Unit at the La Fe Hospital in the Spanish region of Valencia.

According to data from the Spanish Health Ministry, the combination of ibuprofen and codeine is the 10th most used type of opioid in Spain and accounts for 1.17% of the total consumption of this type of drug. The defined daily doses (DDD) per thousand inhabitants per day is 0.083, according to the data. In Spain, consumption of the drug is on a downward trend: it has fallen by 71% since 2011, when it was at 0.2915.

“On the pain treatment scale, the combination of ibuprofen and codeine would be the third level. The first is paracetamol and Nolotil [as metamizole is known in Spain]. The second is NSAIDs. And for more severe pain, other types of opioids are used. But, as the EMA says, it is not a good option for prolonged treatments. At its level, moreover, [ibuprofen and codeine] have been displaced by other combinations such as tramadol with paracetamol,” explained Vicente Baos, a Madrid family doctor.

The EMA warned that the prolonged use of codeine with ibuprofen can also lead to addiction due to the addictive properties of the opioid. This, in turn, increases the risk of the dangerous side effects, it said.

“The committee reviewed several cases of renal, gastrointestinal and metabolic toxicities that have been reported in association with cases of abuse of and dependence from codeine with ibuprofen combinations, some of which have been fatal,” the EMA’s PRAC said in the warning. “The PRAC found that, when taken at higher than recommended doses or for a prolonged period of time, codeine with ibuprofen can cause damage to the kidneys, preventing them from removing acids properly from the blood into the urine (renal tubular acidosis). Kidney malfunction can also cause very low levels of potassium in the blood.”

The EMA warned that there are medicines containing codeine with ibuprofen that are available without a prescription in the European Union. The product information for these combination drugs will now need to be updated to include the EMA’s warning, a process that has already begun, but may take some weeks to complete. According to an AEMPS source, additional measures, such as withdrawing codeine with ibuprofen combinations, are not necessary.


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